4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one dopamine autoreceptor agonists

ABSTRACT

Disclosed are compounds of the formula ##STR1## wherein: R 1  is hydrogen or C 1  -C 6  alkyl; 
     R 2  is selected from hydrogen, straight-chain and branched C 1  -C 10  alkyl, cyclohexylmethyl or --(CH 2 ) m  Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from C 1  -C 6  alkyl, halogen, C 1  -C 6  alkoxide and trifluoromethyl; 
     or NR 1  R 2  is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3, 4-tetrahydroisoquinolin-2-yl; 
     m is 1-5; 
     n is 1 or 2; 
     R 3  is hydrogen or C 1  -C 6  alkyl; 
     Y is halogen, C 1  -C 6  alkyl, and C 1  -C 6  alkoxy; 
     or a pharmaceutically acceptable salt thereof, which are dopamine autoreceptor agonists and as such are useful in the treatment of schizophrenia, Parkinson&#39;s disease, Tourette&#39;s syndrome, alcohol addiction and drug addiction.

This application is a divisional application of U.S. Ser. No.09/025,083, filed Feb. 17, 1998, U.S. Pat. No. 5,990,144 (not yet known)which claims the benefit of prior U.S. Provisional application No.60/038,682 filed Feb. 18, 1997.

FIELD OF INVENTION

This invention relates to a series of4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-ones having dopaminergicproperties and thus have utility in treating Parkinson's disease,Tourette's syndrome, schizophrenia, and alcohol and drug addiction.

BACKGROUND OF THE INVENTION

The compounds of this invention are dopamine agonists having variousdegrees of intrinsic activity and are essentially free fromextrapyramidal side effects. Some of the compounds are selectiveautoreceptor agonists, and therefore partial agonists (i.e. activateonly autoreceptors versus postsynaptic D₂ dopamine receptors). Effortsto induce antipsychotic activity with dopamine autoreceptor agonistshave been successful (Dorsini et al., Adv. Biochem. Psychopharmacol.,16, 645-648, 1977; Tamminga et al., Science, 200, 567-568; and Tammingaet al., Psychiatry, 398-402, 1986).

As selective autoreceptor agonists, the invention compounds providefunctional modulation of the dopamine systems of the brain without theexcessive blockade of the postsynaptic dopamine receptors which havebeen observed to be responsible for the serious side effects frequentlyexhibited by agents found otherwise clinically effective for thetreatment of schizophrenia Activation of the dopamine autoreceptorsresults in reduced neuronal firing a well as inhibition of dopaminesynthesis and release and therefore provides a means of controllinghyperactivity of the dopaminergic systems.

The compounds of this invention were also found to have high intrinsicactivity and therefore they can behave as the natural neurotransmitter,i.e., as full agonists. As such, they are useful in the treatment ofdiseases having abnormal concentrations of dopamine could be used asdopamine surrogates such as schizophrenia, Parkinson's disease andTourette's syndrome. Such agents are partial agonists at thepostsynaptic dopamine D₂ receptor and are thereby useful in thetreatment of alcohol and drug addiction.

In the Belgian patent 850,166, Ciba-Geigy discloses compoundsrepresented by the compound of the formula below which have both a andP-adrenergic properties and are useful as cardiovascular andantihypertensive agents. ##STR2##

SUMMARY OF THE INVENTION

Compounds of this invention are4-aminoalkoxy-1,3-dihydro-benzoimidazol-2-ones which are illustrated byFormula I below ##STR3## wherein: R¹ is hydrogen or C₁ -C₆ alkyl;

R² is selected from hydrogen, straight-chain and branched C₁ -C₁₀ alkyl,cyclohexylmethyl or --(CH₂)_(m) Ar where Ar is phenyl, naphthyl,thienyl, furanyl or pyridinyl, each optionally substituted by one or twosubstituents selected independently from C₁ -C₆ alkyl, halogen, C₁ -C₆alkoxide and trifluoromethyl;

or NR¹ R² is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1, 2, 3,4-tetrahydroisoquinolin-2-yl;

m is 1-5;

n is 1 or 2;

R³ is hydrogen or C₁ -C₆ alkyl;

Y is halogen, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy;

and the pharmaceutically acceptable salts thereof.

Acid addition salts can be formed with an invention compound and apharmaceutically acceptable acid including, but not limited to, thehydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate,acetate, fumarate, succinate, citrate, maleate, lactate, and benzoatesalts.

The compounds of this invention are dopamine autoreceptor agonists, thatis, they serve to modulate the synthesis and release of theneurotranmitter dopamine. They are thus useful for treatment ofdisorders of the dopaminergic system, such as schizophrenia, Parkinson'sdisease and Tourette's syndrome. Such agents are partial agonists at thepostsynaptic dopamine D₂ receptor and are thereby useful in thetreatment of alcohol and drug addiction.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I are generally prepared by the overallsequence depicted in Schemes I-IV. When one or both of R¹ and R² ishydrogen, it is desirable to protect the basic nitrogen with a suitableprotecting group such as the trifluoroacetyl group or t-butyloxycarbonylgroup. Scheme I outlines a procedure to prepare an invention compoundwhere R² and R³ are H. ##STR4##

Scheme II shows a synthetic route for invention compounds where R³ isnot H. ##STR5##

Scheme III shows a synthetic route for invention compounds where neitherof R¹ and R² is H. ##STR6##

Scheme IV shows the procedure used to prepare an intermediate where Y isCl. ##STR7##

The following specific examples illustrate the synthetic procedures forthe preparation of intermediates and invention compounds and should notbe construed as limiting the scope of this disclosure. Those skilled inthe art of organic synthesis may be aware of still other routes toprepare invention compounds. Reactants and intermediates are eithercommercially available or can be prepared according to standardliterature procedures.

Intermediate 1a 2-(2-Chloro-ethoxy)-6-nitro-phenylamine

Method 1.

To a solution of 2-amino-3-nitrophenol (5.0 g, 32.4 mmol),triphenylphosphine (12.8 g, 48.7 mmol) and 2-chloroethanol (3.9 g, 48.7mmol) in tetrahydrofuran (120 mL) at 0-5° C. was added over 30 min asolution of diethyl azodicarboxylate (8.5 g, 48.7 mmol) intetrahydrofuran (75 mL). The mixture was warmed to 23° C. and stirredfor 18 hr. The solvent was removed under vacuum to give a dark brownoil. Purification by chromatography (1.3 kg silica gel, 30%hexane--ethyl acetate) afforded 3.1 g (44.2%) of an orange solid, mp71-73° C.; MS (+)PBEI m/e 216/218 (M⁺).

Elemental analysis for C₈ H₉ ClN₂ O₃ : Calc'd: C, 44.36; H, 4.19; N,12.93. Found: C, 44.45; H, 4.02; N, 12.97.

Method 2.

A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol),1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g,0.252 mol) and 2-butanone (750 mL) was refluxed for 24 hr. The mixturewas cooled, filtered and the solids were washed with ethyl acetate. Thefiltrate was concentrated to an oily residue that was dissolved in ethylacetate (500 mL). The organic layer was washed with 1 N sodium hydroxide(250 mL), water (500 mL), and brine (2×500 mL), dried over anhydrousmagnesium sulfate. Concentration of the filtered solution andtrituration of the residue with hexane afforded 37.8 g (84.6%) ofproduct as an orange solid, mp 71-73° C.; MS (+)PBEI m/e 216/218 (M⁺)

Intermediate 1b 2-(3-Bromo-propoxy)-6-nitro-phenylamine

Following the procedure of method 2 above, and using 1,3-dibromopropane,the tide compound was as a yellow solid, (78.7%) mp 88-89° C.; MS EI m/e274/276 (M⁺).

Elemental analysis for C₉ H₁₁ BrN₂ O₃ : Calc'd: C, 39.29; H. 4.03; N,10.18. Found: C, 39.71; H, 3.91; N, 10.27.

Intermediate 2a 2-(2-Benzylamino-ethoxy)-6-nitro-phenylamine

A mixture of 2-(2-chloro-ethoxy)-6nitro-phenylamine (1a, 3.0 g, 13.8mmol) and benzylamine (9.0 g, 84.0 mmol) was heated neat at 100-110° C.for 6 hr. The excess benzylamine was removed by distillation undervacuum (70-75° C./0.1 mm). The residue was poured into 1 N sodiumhydroxide (300 mL) and extracted with ethyl acetate (2×, 300 mL). Thecombined organic layer was washed with water (2×, 300 mL) and brine (300mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate,filtered, and the solvent removed under vacuum to give 5.1 g of crudered oil. Purification by chromatography (500 g silica gel, ethylacetate: 2 M NH₃ in methanol, 20:1) afforded 3.54 g (89.3%) of a redsemi-solid, mp 33-60° C.; MS EI m/e 287 (M⁺).

Elemental analysis for C₁₅ H₁₇ N₃ O₃ : Calc'd: C, 62.71; H, 5.96; N,14.62. Found: C, 62.64; H, 6.04; N, 14.23.

¹ DMSO can be used as a solvent in this reaction.

Using this general procedure and utilizing2-(2-chloro-ethoxy)-6-nitro-phenylamine or2-(3-bromo-propoxy)-6-nitro-phenylamine or4-chloro-2-(2-chloro-ethoxy)-6-nitro-phenylamine and4methyl-benzylamine, 1-naphthalene-methylamine,4-tert-butyl-benzylamine, thiophene-2-methyl-amine,4-chloro-benzylamine, thiophene-3-methyl-amine,1,2,3,4-tetrahydroisoquinoline or 3-phenyl-1-propylamine produced thefollowing intermediates 2b-2l, respectively:

2b 2-[2-(4-Methyl-benzylamino)-ethoxy]-6-nitro-phenylamine as a yellowsolid (89%), mp 55-57° C.; EI m/e 301 (M⁺).

Elemental analysis for C₁₆ H₁₉ N₃ O₃ : Calc'd: C, 62.71; H, 5.96; N,14.62. Found: C, 62.64; H, 6.04; N, 14.23.

2c 2-(3-Benzylamino-propoxy)-6-nitro-phenylamine as a viscous orange oil(85.5%); MS EI m/e 301 (M⁺).

Elemental analysis for C₁₆ H₁₉ N₃ O₃ : Calc'd: C, 63.77; H, 6.36; N,13.94. Found: C, 63.66; H, 6.28; N, 13.89.

2d 2-{2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-6-nitro-phenylamine as ayellow solid (76.3%), mp 66-67° C.; MS EI m/e 337 (M⁺).

Elemental analysis for C₁₉ H₁₉ N₃ O₃ : Calc'd: C, 67.64; H, 5.68; N,12.45. Found: C, 67.20; H, 5.66; N, 12.26.

2e 2-[2-(4-tert-Butylbenzylamino)-ethoxy]-6-nitro-phenylamine as anorange viscous oil (83.3%); MS EI m/e 343 (M⁺).

Elemental analysis for C₁₉ H₂₅ N₃ O₃.0.25 H₂ O: Calc'd: C, 65.59; H,7.39; N, 12.07. Found: C, 65.89; H, 7.20; N, 11.94.

2f 2-Nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine as ared semi-solid material (88.5%); MS EI m/e 389 (M⁺).

Elemental analysis for C₁₃ H₁₅ N₃ O₃ S: Calc'd: C, 53.23; H, 5.15; N,14.32. Found: C, 52.86; H, 4.93; N, 14.15.

2 g 2-[2-(4-Chloro-benzylamino)-ethoxy]-6-nitro-phenylamine as an orangesolid (87.8%), mp 61-62° C.; MS EI m/e 322/324 (M⁺).

Elemental analysis for C₁₅ H₁₆ N₃ O₃.0.25 H₂ O: Calc'd: C, 55.22; H,5.10; N, 12.88. Found: C, 55.27; H, 4.96; N, 12.88.

2h 2-(2-Benzylamino-ethoxy)-4-chloro-6-nitro-phenylamine as aorange-brown colored solid (54.0%), mp 87-88° C.; MS EI m/e 321/323(M⁺).

Elemental analysis for C₁₅ H₁₆ ClN₃ O₃ : Calc'd: C, 55.99; H, 5.01; N,13.06. Found: C, 55.85; H, 4.90; N, 13.13.

2i4-Chloro-2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamineas a yellow solid (44.0%), mp 74-75° C.; MS EI m/e 327/329 (M⁺).

Elemental analysis for C₁₃ H₁₄ ClN₃ O₂ S: Calc'd: C, 47.67; H, 4.33; N,12.75. Found: C, 47.54; H, 4.11; N, 13.06.

2j4-Chloro-2-nitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-phenylamineas a yellow solid (33.3%), mp 77-78° C.; MS EI m/e 327/329 (+).

Elemental analysis for C₁₃ H₁₄ ClN₃ O₂ S: Calc'd: C, 47.67; H, 4.33; N,12.75. Found: C, 47.54; H, 4.18; N, 12.80.

2k 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine asa yellow solid (87.1%), mp 95-97° C.; MS EI m/e 313 (M⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂ : Calc'd: C, 65.16; H, 6.11; N,13.41. Found: C, 64.87; H, 6.11; N, 13.40.

2l 2-Nitro-6-[2-(-phenyl-propylamino)-ethoxy]-phenylamine as a viscousorange oil (83.9%); MS EI m/e 315 (M⁺).

Elemental analysis for C₁₇ H₂₁ N₃ O₃.0.25 H₂ O: Calc'd: C, 63.83; H,6.77; N, 13.14. Found: C, 63.90; H, 6.56; N, 13.07.

Intermediate 3aN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide

To a solution of 2-(2-benzylamino-ethoxy)-6-nitro-phenylamine (2a, 0.5g, 1.74 mmol) and triethylamine (0.32 mL, 3.48 mmol) in anhydrousmethylene chloride (10 mL) at 23° C. was added trifluoroacetic anhydride(0.32 mL, 2.26 mmol). After 2 hr the reaction was diluted with ether andwashed with saturated sodium bicarbonate (3×80 mL) and the organic layerdried over anhydrous magnesium sulfate. Filtration and evaporation ofthe solvent gave 0.55 g (81.7%) of yellow solid, mp 134-135° C.; MS EIm/e 383 (M⁺).

Elemental analysis for C₁₇ H₁₆ F₃ N₃ O₄ : Calc'd: C, 53.27; H, 4.21; N,10.96. Found: C, 53.09; H, 4.35; N, 10.93.

Following this general procedure and using2-[2-(4-methyl-benzylamino)-ethoxy]-6-nitro-phenylamine,2-(3-benzylamino-propoxy)-6-nitro-phenylamine,2-{2-[(naphthalen-1-ylmethyl)-amino]-ethoxy}-6-nitro-phenylamine,2-[2-(4-tert-butylbenzylamino)-ethoxy]-6nitro-phenyl-amine,2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine,2-[2-(4-chloro-benzylamino)-ethoxyl-6-nitro-phenylamine,2-(2-benzylamino-ethoxy)4-chloro-6-nitro-phenylamine,4-chloro-2-nitro-6-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-phenylamine,4chloro-2-nitro-6-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-phenylamineand 2-nitro-6-[2-(3-phenyl-propylamino)-ethoxy]-phenylamine gaverespectively:

3bN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)acetamideas a yellow solid (79%), mp 172-173° C.; MS EI m/e 397 (M⁺).

Elemental analysis for C₁₈ H₁₈ F₃ N₃ O₄ : Calc'd: C, 54.41; H, 4.57; N,10.58. Found: C, 54.34; H, 4.33; N, 10.53.

3cN-[3-(2-Amino-3-nitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamideasa yellow solid (67.8%), mp 92-93° C.; MS EI m/e 397 (M⁺).

Elemental analysis for C₁₈ H₁₈ F₃ N₃ O₄ : Calc'd: C, 54.41; H, 4.57; N,10.58. Found: C, 54.30; H, 4.50; N, 10.50.

3dN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamideas a yellow-orange colored solid (75.3%), mp 133-135° C.; MS EI m/e 433(M⁺).

Elemental analysis for C₂₁ H₁₈ F₃ N₃ O₄ : Calc'd: C, 58.20; H, 4.19; N,9.70. Found: C, 58.28; H, 4.07; N, 9.48.

2eN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamideas a yellow solid (82.0%), mp 80-82° C.; MS EI m/e 439 (M⁺).

Elemental analysis for C₂₁ H₂₄ F₃ N₃ O₄ : Calc'd: C, 57.40; H, 5.51; N,9.56. Found: C, 57.09; H, 5.31; N, 9.40.

3fN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideas a yellow solid (77.4%) mp 143-144° C.; MS EI m/e 389 (M⁺).

Elemental analysis for C₁₅ H₁₄ F₃ N₃ O₄ S: Calc'd: C, 46.27; H, 3.62; N,10.79. Found: C, 46.19; H, 3.39; N, 10.64.

3 gN-[2-(2-Amino-3-nitro-phenoxy)-ethyl]-N-(4-chloro-benzyl)-2,2,2-trifluoro-acetamideas a yellow solid (84.0%), mp 138-139° C.; MS (+)FAB m/e 418/420 (M+H³⁰)

Elemental analysis for C₁₇ H₁₅ ClF₃ N₃ O₄ : Calc'd: C, 48.88; H, 3.62;N, 10.06. Found: C, 48.66; H, 3.47; N, 9.82.

3hN-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamideas a yellow solid (67.9%), mp 106-108° C.; MS (+)FAB, m/e 418/420(M+H⁺).

Elemental analysis for C₁₇ H₁₅ ClF₃ N₃ O₄ : Calc'd: C, 48.88; H, 3.62;N, 10.06. Found: C, 48.96; H, 3.50; N, 10.03.

3iN-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideas a yellow solid (59.6%), mp 97-98° C.; MS EI m/e 423/425 (M⁺).

Elemental analysis for C₁₅ H₁₃ ClF₃ N₃ O₄ S: Calc'd: C, 42.51; H, 3.09;N, 9.92. Found: C, 42.37; H, 2.97; N, 9.84.

3jN-[2-(2-Amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamideas a yellow solid (80.0%), mp 149-150° C.; MS EI m/e 423/425 (M⁺).

Elemental analysis for C₁₅ H₁₃ ClF₃ N₃ O₄ S: Calc'd: C, 42.51; H, 3.09;N, 9.92. Found: C, 42.02; H, 2.95; N, 9.78.

3kN-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamideas a yellow solid (72.6%), mp 81-82° C.; MS EI m/e 411 (M⁺).

Elemental analysis for C₁₉ H₂₀ F₃ N₃ O₄ : Calc'd: C, 55.47; H, 4.90; N,10.21. Found: C, 55.57; H, 4.66; N, 10.23.

Intermediate 4aN-Benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide

To a mixture ofN-[2-(2-ano-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide(3a, 2.4 g, 6.26 mmol) and 10% palladium on carbon (0.40 g) in ethanol(200 mL) at 50-55° C. was added a solution of hydrate hydrate (2.0 g) inethanol (25 mL). The reaction was allowed to stir for 18 hr at 23° C.,then the catalyst filtered through solka floc and the solvent removedunder vacuum to afford 1.96 g (88.9%) of an amber-colored oil.Crystallization from ethyl acetate--hexane gave a white solid, mp118-119° C.; MS (+)FAB m/e 354 (M+H⁺).

Elemental analysis for C₁₇ H₁₈ F₃ N₃ O₂ : Calc'd: C, 56.58; H, 4.72; N,12.38. Found: C, 57.49; H, 5.10; N, 11.86.

Following the above procedure and utilizingN-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)acetamide,N-[3-(2-amino-3-nitro-phenoxy)-propyl]-N-benzyl-2,2,2-trifluoro-acetamide,N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide,N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-acetamide,N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide,N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-(4-chlorobenzyl)-2,2,2-trifluoro-acetamide,N-[2-(2-ano-5-chloro-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide,N-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide,andN-[2-(2-amino-5-chloro-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamideafforded respectively:

4bN-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamideas a white solid (85.0%), mp 94-96° C.; MS EI m/e 367 (M⁺).

Elemental analysis for C₁₈ H₂₀ F₃ N₃ O₂ : Calc'd: C, 58.85; H, 5.49; N,11.44. Found: C, 58.91; H, 5.32; N, 11.45.

4c N-Benzyl-N-[3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trifluoro-acetamideas a white solid (86.5%), mp 56-58° C.; MS EI m/e 367 (M⁺).

Elemental analysis for C₁₈ H₂₀ F₃ N₃ O₂ : Calc'd: C, 58.85; H, 5.49; N,11.44. Found: C, 59.00; H, 5.42; N, 11.48.

4dN-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamideas a viscous yellow oil (63.0%); MS (+)FAB m/e 404 (M+H⁺).

Elemental analysis for C₂₁ H₂₀ F₃ N₃ O₂ : Calc'd: C, 62.53; H, 5.00; N,10.42. Found: C, 62.45; H, 4.98; N, 10.20.

4eN-(4-tert-Butyl-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamideas a viscous brown oil (72.7%); MS EI m/e 409 (M⁺).

4fN-[2-(2,3-Diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideas a white solid (41.0%), mp 72-74° C.; MS (+)FAB m/e 404 (M+H⁺).

Elemental analysis for C₁₅ H₁₆ F₃ N₃ O₂ S: Calc'd: C, 50.13; H, 4.49; N,11.69. Found: C, 50.09; H, 4.38; N, 11.59.

4 gN-(4-Chloro-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamideas a brown oil (80.9%); MS EI m/e 387/389 (M⁺).

Elemental analysis for C₁₇ H₁₇ ClF₃ N₃ O₂ : Calc'd: C, 52.65; H, 4.42;N, 10.84. Found: C, 52.47; H, 4.51; N, 10.60.

4hN-Benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamideas a viscous brown oil (76.2%); MS EI m/e 387/389 (M⁺).

Elemental analysis for C₁₇ H₁₇ ClF₃ N₃ O₂ : Calc'd: C, 52.65; H, 4.42;N, 10.84. Found: C, 52.47; H, 4.39; N, 10.90.

4iN-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideas a viscous brown oil (71.4%); MS EI m/e 393/395 (M⁺).

Elemental analysis for C₁₅ H₁₅ ClF₃ N₃ O₂ S: Calc'd: C, 45.75; H, 3.84;N, 10.67. Found: C, 45.58; H, 3.93; N, 10.64.

4iN-[2-(2,3-Diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamideas a viscous brown oil (75.0%); MS EI m/e 393/395 (M⁺).

Elemental analysis for C₁₅ H₁₅ ClF₃ N₃ O₂ S: Calc'd: C, 45.75; H, 3.84;N, 10.67. Found: C, 45.39; H, 3.84; N, 10.56.

Intermediate 5aN-Benzyl-2,2,2-trifluoro-N-[2.(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide

A mixture ofN-benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide(0.28 g, 0.804 mmol) and diimidazole carbonyl (0.326 g, 2.0 mmol) inanhydrous tetrahydrofuran (10 mL) was stirred at 23° C. for 2 hr. Thereaction was poured into water and extracted with ethyl acetate (2×150mL). The organic layer dried over anhydrous magnesium sulfate, filtered,and the solvent removed under vacuum. Purification by chromatography (60g silica gel, ethyl acetate: hexane: 2 M NH₃ in methanol (15:5:1))afforded 0.29 g (94.8%) of a colorless oil. Crystallization from hexanegave a white solid, mp 121-123° C.; MS EI m/e 379 (M⁺).

Elemental analysis for C₁₈ H₁₆ F₃ N₃ O₃ : Calc'd: C, 56.99; H, 4.25; N,11.08. Found: C, 57.09; H, 4.07; N, 11.10.

UtilizingN-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-(4-methyl-benzyl)-acetamide,N-benzyl-N-[3-(2,3-diamino-phenoxy)-propyl]-2,2,2-trifluoro-acetamide,N-[2-(2,3diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-naphthalen-1-ylmethyl-acetamide,N-(4-tert-butyl-benzyl-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide,N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide,N-(4-chloro-benzyl)-N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide,N-benzyl-N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide,N-[2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideandN-2-(2,3-diamino-5-chloro-phenoxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamidein the above general procedure afforded respectively:

5b2,2,2-Trifluoro-N-(4-methyl-benzyl)-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide·0.1ethyl acetate as a white solid (96.6%), mp 194-196° C.; MS (+)FAB m/e394 (M+H⁺).

Elemental analysis for C₁₉ H₁₈ F₃ N₃ O₃.0.1 C₄ H₈ O₂ Calc'd: C, 57.94;H, 4.71; N, 10.45. Found: C, 57.90; H, 4.60; N, 10.19.

5c N-Benzyl-2,2,2-trifluoro-N-[3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propyl]-acetamide as a white solid(86.0%), mp 114-116° C.; MS (+)FAB m/e 394 (M+H⁺).

Elemental analysis for C₁₉ H₁₈ F₃ N₃ O₃ Calc'd: C, 58.01; H, 4.61; N,10.68. Found: C, 57.67; H, 4.37; N, 10.49.

5d2,2,2-Trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamideas a white solid (90.0%), mp 88-90° C.; MS EI m/e 429 (M⁺).

Elemental analysis for C₂₂ H₁₈ F₃ N₃ O₃ Calc'd: C, 61.54; H, 4.23; N,9.79. Found: C, 61.34; H, 4.25; N, 9.52.

5eN-(4-tert-Butyl-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamideas a white solid (84.9%), mp 184-185° C.; MS EI m/e 435(M⁺).

Elemental analysis for C₂₂ H₂₄ F₃ N₃ O₃ Calc'd: C, 60.68; H, 5.55; N,9.65. Found: C, 60.59; H, 5.55; N, 9.66.

5f2,2,2-Trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-N-thiophen-2-ylmethyl-acetamideas a white solid (73.3%), mp 49-50° C.; MS EI m/e 385 (M⁺).

5 gN-(4-Chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamideas a white solid (56.7%), mp 190-192° C.; MS(+)FAB m/e 414/416(M+H⁺).

Elemental analysis for C₁₈ H₁₅ ClF₃ N₃ O₃ Calc'd: C, 52.25; H, 3.65; N,10.16. Found: C, 52.28; H, 3.55; N, 10.20.

5hN-Benzyl-N-[2-(6-chloro-2-oxo-2,3-dihydro-H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-acetamideas a white solid (60.0%), mp 171-173° C.; MS (+)APCI m/e 414.2/416.2(M+H⁺).

Elemental analysis for C₁₈ H₁₅ ClF₃ N₃ O₃ Calc'd: C, 52.25; H, 3.65; N,10.16. Found: C, 52.10; H, 3.56; N, 9.96.

5iN-[2-(6-Chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamideas a white solid (70.1%), mp 153-154° C.; MS EI m/e 419/421 (M⁺).

Elemental analysis for C₁₆ H₁₃ ClF₃ N₃ O₃ S: Calc'd: C, 45.78; H, 3.12;N, 10.01. Found: C, 45.85; H, 3.02; N, 9.73.

5jN-[2-(6-Chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamideas a white solid (77.8%), mp 152-153° C.; MS EI m/e 419/421 (M⁺).

Elemental analysis for C₁₆ H₁₃ ClF₃ N₃ O₃ S: Calc'd: C, 45.78; H, 3.12;N, 10.01. Found: C, 45.86; H, 2.93; N, 9.76.

Intermediate 6N-[2-(2{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide

To a suspension ofN-[2-(2-amino-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide(4.95 g, 12.9 mmol) in anhydrous methylene chloride (50 mL) at roomtemperature was added trifluoroacetic anhydride (3.18 g, 15.1 mmol).After 15 min the reaction was diluted with ether and washed withsaturated sodium bicarbonate (3×80 mL) and the organic layer dried overanhydrous magnesium sulfate. Upon filtration and evaporation of thesolvent gave 5.84 g (94.4%) of yellowish white solid, mp 114-115° C.; MSFAB m/e 480 (M+H⁺).

Elemental analysis for C₁₉ H₁₅ F₆ N₃ O₅ Calc'd: C, 47.61; H, 3.15; N,8.77. Found: C, 47.35; H, 2.94; N, 8.69.

Intermediate 7N-[2-(1-Methyl-2-{2,2,2-Trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide

A suspension of potassium carbonate (1.44 g, 10.4 mmol),N-[2-(2-{2,2,2-trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide(1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previouslyfiltered through basic alumina) in anhydrous dimethylsulfoxide (11 mL)was allowed to stir at room temperature for 24 h. The reaction mixturewas poured into methylene chloride (200 mL) and extracted with water(2×80 mL). The organic layer was dried over anhydrous magnesium sulfate,filtered, and the solvent removed under vacuum to afford a yellow thickoil. Purification by chromatography (30% ethyl acetate-hexanes) afforded960 mg (93.3%) of a light yellow solid, mp 90-92.5° C.; MS m/e EI 493(M⁺).

Elemental analysis for C₂₀ H₁₇ F₆ N₃ O₅ Calc'd: C, 48.70; H, 3.47; N,8.57. Found: C, 48.50; H, 3.27; N, 8.39.

Intermediate 8 N-Benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine

A suspension of potassium carbonate (2.52 g, 18.2 mmol) andN-[2-1-methyl-(2-{2,2,2-trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide(900 mg, 1.82 mmol) in methanol-water (50 mL:3 mL) was heated to refluxfor 2 h then the solvent was evaporated and the residue dissolved inmethylene chloride (100 mL) and extracted with water (80 mL). Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andthe solvent removed under vacuum. The residue was further purified bypassing through a short pad of silica to afford 505 mg (92.1%) ofN-benzyl-2-(methylamino-3-nitro-phenoxy)ethylamine as a red oil; MS FABm/e 302 (M+H⁺).

Intermediate 9N-Benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acidtert-butyl ester

A solution of N-benzyl-2-(2-methylamino-3-nitro-phenoxy)-ethylamine (480mg, 1.59 mmol) and di-tert-butyl dicarbonate (348 mg, 1.59 mmol) inanhydrous tetrahydrofuran (6 mL) was allowed to stir for 3 hr. Thereaction mixture was poured into methylene chloride (80 mL) and washedwith water (50 mL). The organic layer dried over anhydrous magnesiumsulfate, filtered, and the solvent evaporated to afford 593 mg (93%) ofan orange solid, mp 91-93° C.; MS m/e EI 401 (M⁺).

Elemental analysis for C₂₁ H₂₇ N₃ O₅ Calc'd: C, 62.83; H, 6.78; N,10.47. Found: C, 62.78; H, 6.53; N, 10.51.

Intermediate 10N-Benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamic acidtert-butyl ester

To a mixture ofN-benzyl-[2-(2-methylamino-3-nitro-phenoxy)-ethyl]-carbamic acidtert-butyl ester (520 mg, 1.30 mmol) and 10% palladium on carbon (120 mg) in ethanol (40 mL) at 50° C. was added a solution of hydrazine hydrate(1.3 g) in ethanol (10 mL). The reaction was allowed to stir for 3 hrthen the catalyst filtered through celite and the solvent removed.Purification by chromatography (30% ethyl acetate-hexane) afforded 380mg (78.9%) of a clear oil; MS EI m/e 371 (M⁺); IR (film) 3400,3350,1680cm-1.

Intermediate 11N-Benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl]-carbamicacid tert-butyl ester

A mixture of N-benzyl-[2-(2-methylamino-3-amino-phenoxy)-ethyl]-carbamicacid tert-butyl ester (330 mg, 0.89 mmol) and diimidazole carbonyl (577mg, 3.56 mmol) in anhydrous tetrahydrofuran (30 mL) was stirred a roomtemperature for 0.5 h and then heated to reflux for 3 h. The reactionwas poured into water and extracted with ethyl acetate (2×150 mL). Theorganic layer dried over anhydrous magnesium sulfate, filtered, and thesolvent removed. Purification by chromatography (50% ethylacetate-hexane) afforded 268 mg (75.8%) of a foam; MS FAB m/e 398(M+H⁺); IR (KBr) 3420, 3250, 1690 (bs) cm-1.

Intermediate 123-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine

The general procedure used in intermediate 4 using2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k)afforded3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-benzene-1,2-diamine as asolid (95%), mp 76-77° C. This material was characterized as thedihydrochloride 0.4 H₂ O salt; MS EI m/e 283 (M⁺).

Elemental analysis for C₁₇ H₂₁ N₃ O.2 HCl.0.4 H₂ O: Calc'd: C, 56.17; H,6.60; N, 11.56. Found: C, 56.15; H, 6.68; N, 11.25.

Intermediate 13 4-Chloro-2-(2-chloro-ethoxy)-6-nitro-phenylamine

A solution of 2-(2chloro-ethoxy)-6nitro-phenylamine (1a, 30.0 g, 0.14mol), N-chlorosuccinamide and acetonitrile (1.3 L) was refluxed for 4hr. The mixture was concentrated under vacuum and the residue wasdiluted with ethyl acetate (500 mL). The organic layer was washed withwater (2×, 250 mL) and brine (250 mL), dried over anhydrous magnesiumsulfate, filtered, and the solvent removed under vacuum to give anorange solid residue. Crystallization from ethyl acetate-hexane gave33.5 g (95.3%) as orange solid, mp 109-110° C.; MS EI m/e 250/252/254(M⁺).

Elemental analysis for C₈ H₈ Cl₂ N₂ O₃ : Calc'd: C, 38.27; H, 3.21; N,11.16. Found: C, 38.15; H, 3.10; N, 10.96.

EXAMPLE 1 4-(2-Benzylamino-ethoxy)-1,3-dihydro-benzoimidazol-2-one

A suspension of potassium carbonate (1.15 g, 8.34 mmol) andN-benzyl-2,2,2-trifluoro-N-[2-(2-oxo-1,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide(0.38 g, 1.00 mmol) in methanol-water (30 mL:2 mL) was heated to refluxfor 2 hr then the solvent was evaporated and the residue dissolved inethyl acetate (100 mL) and extracted with water (80 mL). The organiclayer was dried over anhydrous magnesium sulfate, filtered, and thesolvent removed under vacuum to give the tide compound as a white solid,mp 132-135° C. Without further purification, this material was dissolvedin ethyl acetate methanol (1:1) and treated with an excess amount of 1 NHCl in ether to afford 0.30 g (75.0%) of the hydrochloride salt as alight tan-colored solid, mp 230-233° C.: MS EI m/e 283 (M⁺).

Elemental analysis for C₁₆ H₁₇ N₃ O₂.HCl Calc'd: C, 60.09; H, 5.67; N,13.14. Found: C, 59.84; H, 5.59; N, 12.92.

EXAMPLE 24-[2-(4-Methyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and utilizing2,2,2-trifluoro-N-(4-methyl-benzyl)-N-[2-(2-oxo-2,3dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide·0.1ethyl acetate (5b) afforded the title compound as a white solid (64.5%),mp 162-163° C.; MS (+)FAB m/e 298 (M+H⁺). Treatment of the free basewith ethereal HCl gave a white solid (90.0%), mp 244-246° C.: MS (+)FABm/e 298 (M+H⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂.1.0 HCl.1.7 H₂ O Calc'd: C, 56.17;H, 6.46; N, 11.56. Found: C, 55.94; H, 6.05; N, 11.42.

EXAMPLE 34(7)-(2-Benzylamino-ethoxy)-1-(3)-methyl-1,3-dihydro-benzoimidazol-2-one

To a solution ofN-benzyl-[2-(2-oxo-1,3-dihydro-benzoimidazol-4-yloxy)-ethyl]-carbamicacid tert-butyl ester in anhydrous methylene chloride (7 mL) was addedtrifluoracetic acid (3 mL). After 15 min the reaction was poured intoaqueous saturated sodium bicarbonate (150 mL) and extracted withmethylene chloride (2×150 mL). The organic layer dried and the solventremoved to afford 170 mg (87%) a white solid: mp 137-138° C.; MS FAB 298(M+H⁺). The fumarate salt was prepared by adding a solution of the freebase (165 mg) in warm isopropanol (15 mL) to an excess of fumaric acidin warm isopropanol (20 mL). Upon completion of addition crystals beganforming and the mixture was allowed to cool to room temperature and thecrystals filtered to afford 203 mg of fumarate salt, mp 201.5-202.5° C.;MS ESI m/e 298 (M+H⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂.C₄ H₄ O₄ Calc'd: C, 61.01; H, 5.61;N, 10.16. Found: C, 60.73; H, 5.36; N, 9.95.

EXAMPLE 4 4-(3-Benzylamino-propoxy)-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-benzyl-2,2,2-trifluoroN-[3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propyl]-acetamide(5c) afforded the title compound as a light yellow solid foam (90.4%);MS EI m/e 297 (M⁺). Treatment of the free base with ethereal HCl gavethe hydrochloride salt as a white solid (63.9%), mp 243-244° C.: MS EIm/e 297 (M⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂.HCl: Calc'd: C, 61.17; H, 6.04; N,12.59. Found: C, 60.92; H, 5.95; N, 12.41.

EXAMPLE 54-{2-[(Naphthalen-1-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and using2,2,2-trifluoro-N-naphthalen-1-ylmethyl-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4yloxy)-ethyl]-acetamide(5d) gave the title compound as a white solid (67.4%); MS EI m/e 333(M⁺).

Elemental analysis for C₂₀ H₁₉ N₃ O₂ : Calc'd: C, 72.05; H, 5.74; N,12.60. Found: C, 71.72; H, 5.76; N, 12.22.

Treatment of the free base with ethereal HCl gave the quarter hydrate ofthe HCl as a white solid (63.9%), mp 223-225° C.: MS EI m/e 333 (M⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂.HCl.quarter hydrate: Calc'd: C,64.17; H, 5.52; N, 11.23. Found: C, 64.33; H, 5.42; N, 11.28.

EXAMPLE 64-[2-(4-tert-Butyl-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide(5e) gave the title as a white solid (84.5%); MS EI m/e 339 (M⁺).

Elemental analysis for C₂₀ H₂₅ N₃ O₂ : Calc'd: C, 70.77; H, 7.42; N,12.38. Found: C, 70.59; H, 7.44; N, 12.28.

Treatment of the tide compound with ethereal HCl gave the hemihydratedHCl salt as a white solid, mp 224-226° C.: MS EI m/e 339 (M⁺).

Elemental analysis for C₂₀ H₂₅ N₃ O₂.HCl.hemihydrate: Calc'd: C, 62.41;H, 7.07; N, 10.92. Found: C, 62.64; H, 6.93; N, 10.88.

EXAMPLE 74-{2-[(Thiophen-2-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and using2,2,2-trifluoro-N-[2-(2oxo-2,3-dihydro-1H-benzoimidazol-4yloxy)-ethyl]-N-thiophen-2-ylmethyl-acetamide(5f), the title compound is obtained as a white solid (76.8%); MS EI m/e289 (M⁺).

Elemental analysis for C₁₄ H₁₅ N₃ O₂ S: Calc'd: C, 56.36; H, 5.41; N,14.08. Found: C, 56.42; H, 5.04; N, 14.21.

Conversion of the free base to the HCl salt with ethereal gave a whitesolid, mp 240-241° C.: MS EI m/e 289 (M⁺).

Elemental analysis for C₁₄ H₁₅ N₃ O₂ S.HCl: Calc'd: C, 51.61; H, 4.95;N, 12.90. Found: C, 51.22; H, 4.82; N, 12.70.

EXAMPLE 84-[2-(4-Chloro-benzylamino)-ethoxy]-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-(4-chloro-benzyl)-2,2,2-trifluoro-N-[2-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide(5g), the tide compound is obtained as a white solid (77.6%), mp163-164° C.; MS (+)FAB m/e 318/320 (M+H⁺).

Elemental analysis for C₁₆ H₁₆ ClN₃ O₂ : Calc'd: C, 60.48; H, 5.08; N,13.22. Found: C, 60.17; H, 4.83; N, 13.20.

Treatment of the free base with ethereal HCl yields the hydrochloride asa white solid, mp>250° C.: MS EI m/e 3171319(M⁺).

Elemental analysis for C₁₆ H₁₆ ClN₃ O₂.HCl: Calc'd: C, 54.25; H, 4.84;N, 11.86. Found: C, 54.18; H, 4.76; N, 11.87.

EXAMPLE 94-(2-Benzylamino-ethoxy)-6-chloro-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-(4-chloro-benzyl)-2,2,2-trifluoroN-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-acetamide(5h) afforded the tide compound as a white solid (77.6%), mp 192-193°C.; MS El m/e 3171319 (M⁺).

Elemental analysis for C₁₆ H₁₆ ClN₃ O₂ : Calc'd: C, 60.48; H, 5.08; N,13.22. Found: C, 60.24; H, 5.01; N, 13.09.

Treatment of the free base with ethereal HCl gave the hydrochloride saltas a white solid, mp>250° C.: MS EI m/e 317/319 (M⁺).

Elemental analysis for C₁₆ H₁₆ ClN₃ O₂.HCl: Calc'd: C, 54.25; H, 4.84;N, 11.86. Found: C, 54.23; H, 4.85; N, 11.69.

EXAMPLE 106-Chloro-4-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-2-ylmethyl-acetamide(5i) afforded the title compound as a white solid (89.0%), mp 179-180°C.; MS EI m/e 323/325 (M⁺).

Elemental analysis for C₁₄ H₁₄ ClN₃ O₂ S: Calc'd: C, 51.93; H, 4.36; N,12.98. Found: C, 51.80; H, 4.23; N, 12.96.

Treatment of the title compound with ethereal HCl gave the hydrochlorideas a white solid(90.0%), mp>250° C.: MS EI m/e 323/325 (M⁺).

Elemental analysis for C₁₄ H₁₄ ClN₃ O₂ S.HCl: Calc'd: C, 46.68; H, 4.20;N, 11.66. Found: C, 46.52; H, 4.00; N, 11.57.

EXAMPLE 116-Chloro-4-{2-[(thiophen-3-ylmethyl)-amino]-ethoxy}-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and usingN-[2-(6-chloro-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-2,2,2-trifluoro-N-thiophen-3-ylmethyl-acetamide(5j), the title compound is obtained as a white solid (89.0%), mp182-183° C.; MS (+)FAB m/e 324/326 (M+H⁺).

Elemental analysis for C₁₄ H₁₄ ClN₃ O₂ S: Calc'd: C, 51.93; H, 4.36; N,12.98. Found: C, 51.96; H, 4.30; N, 12.95.

The tide compound was treated with ethereal HCl to obtain thehydrochloride salt as a white solid (90.0% ), mp>250° C.: MS EI m/e323/325 (M⁺).

Elemental analysis for C₁₄ H₁₄ ClN₃ O₂ S.HCl: Calc'd: C, 46.68; H, 4.20;N, 11.66. Found: C, 46.29; H, 4.09; N, 11.51.

EXAMPLE 124-[2-(2,3-Dihydro-1H-isoquinolin-2yl)-ethoxy]-1,3-dihydro-benzoimidazol-2-one

Following the general procedure used in example 1 and using2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-ethoxy]-6-nitro-phenylamine (2k)afforded the title compound as a white solid (63.0%), mp 173-174° C.; MSEI m/e 309 (M⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₂ : Calc'd: C, 69.88; H, 6.19; N,13.58. Found: C, 69.48; H, 6.01; N, 13.55.

Treatment of the free base with ethereal HCl gave a quarter hydrate ofthe hydrochloride salt as a white solid (90.0% ), mp>250° C.: MS EI m/e323/325 (M⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₂.HCl.0.25 H₂ O: Calc'd: C, 61.71; H,5.90; N, 11.99. Found: C, 61.90; H, 5.88; N, 11.97.

EXAMPLE 134-[2-(3-Phenyl-propylamine)-ethoxy]-1,3-dihydro-benzoimidazol-2-one

Following the general procedures used in intermediates 4 and 5 andexample 1,N-[2-(2-amino-3-nitro-phenoxy)-ethyl]-2,2,2-trifluoro-N-(3-phenyl-propyl)-acetamide(3k) afforded the title comound as a white solid; MS (+)FAB m/e 312(M+H⁺).

Elemental analysis for C₁₈ H₂₁ N₃ O₂.0.5 H₂ O: Calc'd: C, 67.48; H.6.92; N, 13.12. Found: C, 67.81; H. 6.76; N, 13.51.

Treatment of the free base with ethereal HCl gave the hydrochloride saltas a white solid (90.9%), mp 243-245° C.; MS (+)FAB m/e 312 (M+H⁺).

Elemental analysis for C₁₈ H₂₁ N₃ O₂.HCl: Calc'd: C, 62.15; H, 6.38; N,12.08. Found: C, 62.06; H, 6.21; N, 11.97.

Pharmacology

A method for determining intrinsic activity at the dopamine D2 receptorwas to recently reported [Lahti et al., Mol. Pharm., 42, 432-438,(1993)]. Intrinsic activity is predicted using the ratio of the"low-affinity agonist" (LowAg) state of the receptor and the"high-affinity agonist" (HighAg) state of the receptor, i.e.LowAg/HighAg. These ratios correlate with the agonist, partial agonist,and antagonist activities of a given compound, which activitiescharacterize a compounds ability to elicit an antipsychotic effect.

Affinity for the dopamine autoreceptor was established by a modificationof the standard experimental test procedure of Seemen and Schaus,European Journal of Pharmacology 203: 105-109, 1991, wherein homogenizedrat striatal brain tissue is incubated with ³ H-quinpirole (Quin.) andvarious concentrations of test compound, filtered and washed and countedin a Betaplate scintillation counter.

High affinity for the dopamine D-2 receptor was established by thestandard experimental test procedure of Fields, et al., Brain Res., 136,578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding,Raven Press, N.Y. (1978) wherein homogenized limbic brain tissue isincubated with ³ H-spiroperidol (Spiper.) and various concentrations oftest compound, filtered and washed and shaken with Hydrofluorscintillation cocktail (National Diagnostics) and counted in a Packard460 CD scintillation counter.

The results of the tests with compounds representative of this inventionare given in the immediately following table

    ______________________________________                                                  IC.sub.50 (nM)                                                                              IC.sub.50 (nM)                                          Example # D.sub.2 Quin. D.sub.2 Spiper Ratio                                ______________________________________                                        1         0.51          60.6     118                                            2 0.29 28.5 98                                                                3 2.92 1346 461                                                               4 125.8 5979 47.5                                                             5 0.60 38.7 64.5                                                              6 0.81 47.8 59                                                                7 0.51 254.6 499.2                                                            8 0.30 99.5 331.7                                                             9 0.48 34.6 70.6                                                              10 0.47 58.0 123.4                                                            11 0.31 67.0 216.1                                                            12 12.0 657.5 55                                                              13 0.30 30.0 100.0                                                          ______________________________________                                    

Pharmaceutical Composition

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient in need thereof. The pharmaceuticalcarrier may be solid or liquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties nsuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carrier may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be as either aliquid or a solid dosage form.

The compounds of this invention may be administered rectally in the formof a conventinal suppository. For administration by intranasal orintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to realease the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient suffering adopamine imbalance must be subjectively determined by the attendingphysician. The variables involved include the severity of thedysfunction, and the size, age, and response pattern of the patient.

Treatment will generally be initiated with small dosages less than theoptimum dose of the compound. Thereafter the dosage is increased untilthe optimum effect under the circumstances is reached. Precise dosagesfor oral, parenteral, nasal, or intrabronchial administration will bedetermined by the administering physician based on experience with theindividual subject treated and standerd madical principles.

Preferably the pharmaceutical composition is in unit dosage form, e.g.,as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage form can be packaged compositions, for example packedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

What is claimed is:
 1. A method of treating diseases in a mama whichrespond to treatment by administration of a dopamine D₂ agonist whichcomprises administration to a mammal in need thereof of atherapeutically effective amount of a compound according to the formula##STR8## wherein: R¹ is hydrogen or C₁ -C₆ alkyl;R² is selected fromhydrogen, straight-chain and branched C₁ -C₁₀ alkyl, cyclohexylmethyl or--(CH₂)_(m) Ar where Ar is phenyl, naphthyl, thienyl, furanyl orpyridinyl, each optionally substituted by one or two substituentsselected independently from C₁ -C₆ alkyl, halogen, C₁ -C₆ alkoxide andtrifluoromethyl; or NR¹ R² is 1, 2, 3, 4-tetrahydroquinolin-1-yl or 1,2, 3, 4-tetrahydroisoquinolin-2-yl; m is 1-5; n is 1 or 2; R³ ishydrogen or C₁ -C₆ alkyl; Y is halogen, C₁ -C₆ alkyl, and C₁ -C₆alkoxy;or a pharmaceutically acceptable salt thereof.
 2. The method oftreatment according to claim 1 wherein the disease treated isschizophrenia.
 3. The method of treatment according to claim 1 whereinthe disease treated is Parkinson's disease.
 4. The method of treatmentaccording to claim 1 wherein the disease treated is Tourette's syndrome.5. The method of treatment according to claim 1, wherein the diseasetreated is alcohol or drug addiction.